SC05.02 Novel Cytotoxic Drugs in Lung Cancer

Abstract

Even in the era of precision medicine and immunotherapy, cytotoxic chemotherapies remain an essential component of lung cancer treatment, both in resectable disease as well as in advanced/metastatic lung cancer. We have chosen to focus on 2 new cytotoxic compounds, which are likely to emerge as new players in the field of lung cancer management. One (named PM1183) has activity in small-cell lung cancer (SCLC), the other TAS-114 has activity in non-small cell lung cancer (NSCLC). PM1183 is a DNA-binding chemotherapy with a new mechanism of action. PM1183 acts as an inhibitor of transcription. Binding of PM1183 to CG-rich motifs, triggers sequential phosphorylation of Pol II and stalling of elongating Pol II. This leads to recruitment of the ubiquitin-proteasome machinery, RNA Pol II degradation, and recruitment of XPF, generation of DNA breaks and induction of apoptosis. PM1183 has been tested in a phase IB trial in combination with doxorubicine. In the dose-finding part: recommended dose (RD) was defined at PM1183 4.0 mg flat dose (FD) or 2.0 mg/m2 + DOX 50 mg/m2 both on day (D)1 every three weeks (q3w). Myelosuppression was dose-limiting (DLT). Compelling activity was observed during escalation phase. It was especially remarkable as 2nd line in SCLC patients: 5 of 7 evaluable pts (71%) had objective partial response (PR) as per RECIST v.1.1. In an expansion cohort of 20 patients, PM1183 and DOX showed outstanding clinical activity: 67% response rate, including 10% of CRs, as 2nd line treatment in SCLC patients. A randomized phase III trial testing PM1183 + DOX is planned and will compare this combination with topotecan or CAV. TAS-114 is a first-in-class oral deoxyuridine triphosphatase (dUTPase) inhibitor that acts as a modulator of the pyrimidine nucleotide metabolic pathway by blocking the conversion of 2’-deoxyuridine-5’-triphosphate (dUTP; FdUTP) into 2’-deoxyuridine-5’-monophophate (dUMP; FdUMP) through reversible inhibition of dUTPase (gatekeeper protein), resulting in the enhanced incorporation of both uracil and fluorouracil into DNA. The activity of TAS-114, administered in combination with thymidine synthase (TS) inhibitors, 5-FU, S-1 or capecitabine, has been studied pre-clinically in various cancer cell lines and animal models. TAS-114 selectively inhibited dUTPase and showed a higher affinity than the substrates of dUTPase, dUTP and FdUTP, inhibition constant values of TAS-114 were 0.13 μM and 0.10 μM, respectively. The antitumor effect of TAS-114 combined with S-1 as compared to that of S-1 alone was investigated in vivo using a xenograft mouse model with NCI-H2228 (human NSCLC). Both regimens were administered orally (TAS-114: 600 mg/kg/day and S-1: 8.3 mg/kg/day vs S-1: 8.3 mg/kg/day through day 1 to 28) and resulted in relative tumor volumes of 1.61% vs 3.04%, p<0.01, inhibition rates of 52.7% vs 10.8%, and body weight changes of 6.8% vs 3.3%, respectively. A phase 1 clinical study of TAS-114 and S-1 combination treatment is currently ongoing to investigate the safety and to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in patients (pts) with advanced refractory solid tumors. TAS-114 and S-1 are administrated orally twice a day for 14 days followed by 7 days resting period for a 21-days cycle at the starting dosage of 5 mg/m2 with the fixed dosage of 25 mg/m2, respectively. To date, a total of 96 pts were enrolled with 37 pts in the dose escalation and 59 pts in the MTD expansion stages. TAS-114 and S-1 were escalated up to 240 mg/m2 and 36 mg/m2, respectively, with 2 DLTs observed at the highest dose level (1 patient with G3 rash and 1 patient with G2 rash/G2 HFS), therefore TAS-114 at 240 mg/m2 and S-1 at 30 mg/m2 was determined to be the MTD and RD. The most common treatment related adverse events were anemia and rash. There were 4 confirmed partial responses observed in 2 non-small cell lung (NSCLC) pts, 1 pancreas pt and 1 colorectal cancer patient to date. Amongst 6 evaluable NSCLC pts to date, there was an overall response rate of 33% (2/6) with 2 confirmed PR and a disease control rate of 100% (6/6). Pharmacodynamics analysis performed on patient tumor specimens treated at MTD indicated TAS-114 target engagement by reductions in the amount of intra-tumoral dUMP, a “surrogate” metabolite indicative of dUTPase inhibition, following TAS-114/S-1 combination as compared to S-1 alone administration. When TAS-114 is administered in combination with S-1, an additional cytocidal antitumor effect to TTP depletion by TS inhibition is expected as TAS-114 inhibits a gatekeeper protein, thereby allowing increased DNA incorporation of both uracil and 5-FU resulting in DNA damage. new cytotoxics, small-cell lung cancer, non-small cell lung cancer